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MsrA Suppresses Inflammatory Activation of Microglia and Oxidative Stress to Prevent Demyelination via Inhibition of the NOX2-MAPKs/NF-κB Signaling Pathway

Authors Fan H, Li D, Guan X, Yang Y, Yan J, Shi J, Ma R, Shu Q

Received 15 July 2019

Accepted for publication 20 February 2020

Published 5 April 2020 Volume 2020:14 Pages 1377—1389

DOI https://doi.org/10.2147/DDDT.S223218

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo


Hua Fan,1,* Damiao Li,1,* Xinlei Guan,2,* Yanhui Yang,1 Junqiang Yan,1 Jian Shi,1 Ranran Ma,3 Qing Shu3

1The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471000, People’s Republic of China; 2Department of Pharmacy, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 3Department of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University, Xi’an 710054, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hua Fan
The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24, Jinghua Road, Jianxi District, Luoyang 471000, Henan Province, People’s Republic of China
Tel +86-18538825892
Email fanhua19851229@126.com
Qing Shu
Department of Pharmacy, Ninth Hospital of Xi’an, Affiliated to Medical College of Xi’an Jiaotong University, No. 151, Eastern Section of South 2nd Ring Road, Xi’an 710054, Shaanxi Province, People’s Republic of China
Tel +86-18627121873
Email shuqinglwz@163.com

Introduction: Demyelination causes neurological deficits involving visual, motor, sensory symptoms. Deregulation of several enzymes has been identified in demyelination, which holds potential for the development of treatment strategies for demyelination. However, the specific effect of methionine sulfoxide reductase A (MsrA) on demyelination remains unclear. Hence, this study aims to explore the effect of MsrA on oxidative stress and inflammatory response of microglia in demyelination.
Methods: Initially, we established a mouse model with demyelination induced by cuprizone and a cell model provoked by lipopolysaccharide (LPS). The expression of MsrA in wild-type (WT) and MsrA-knockout (MsrA-/-) mice were determined by RT-qPCR and Western blot analysis. In order to further explore the function of MsrA on inflammatory response, and oxidative stress in demyelination, we detected the expression of microglia marker Iba1, inflammatory factors TNF-α and IL-1β and intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) activity, as well as expression of the NOX2-MAPKs/NF-κB signaling pathway-related genes in MsrA-/- mice and LPS-induced microglia following different treatments.
Results: MsrA expression was downregulated in MsrA-/- mice. MsrA silencing was shown to produce severely injured motor coordination, increased expressions of Iba1, TNF-α, IL-1β, ROS and NOX2, and extent of ERK, p38, IκBα, and p65 phosphorylation, but reduced SOD activity. Conjointly, our study suggests that Tat-MsrA fusion protein can prevent the cellular inflammatory response and subsequent demyelination through negative regulation of the NOX2-MAPKs/NF-κB signaling pathway.
Conclusion: Our data provide a profound insight on the role of endogenous antioxidative defense systems such as MsrA in controlling microglial function.

Keywords: demyelination, MsrA, NOX2-MAPKs/NF-κB signaling pathway, microglia, oxidative stress, inflammatory activation

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